national taiwan university hanne inez wolff aug. 21st, 2013

Trans-Sialidase’s Role in Chronic Chagas Disease, and it’s Potential for Infection Inhibition by Employing Natural Products National Taiwan UniversityHanne Inez WolffAug. 21st, 2013

Research Proposal• Chagas Disease is affecting 10-15 million people world wide,

especially in rural areas of Latin America. There are two phases to the disease; the acute phase which lasts about 4-8 weeks, and the chronic phase which follows the acute phase. Currently, there are only two drugs to treat Chagas disease, which are both not approved by the FDA, and to get a hold of the drugs, infected individuals must request them through the CDC and follow strict protocols. More importantly, these two drugs, despite their serious side effects, have shown efficiency only in infected individuals with acute Chagas Disease.

• My research is looking at potential Natural Products to treat chronic Chagas Disease via utilizing computational modeling and predictions.

Methodology• Screened and identified “good” PDB structures for docking.• “Good” is defined as experimental and docking overlap• Two docking programs were utilized:• AutoDock 4.0 with plug in• AutoDock Vina

• Three Trans-Sialidase structures were identified as good representations in the PDB: 1MS9, 1MS8, 1S0J

• Both 1MS9, and 1MS8 are from Buschiazzo (2002) article• 1S0J is from Amaya (2004) article

Data Collected from PDB AnalysisExperimental Overlap Binding Affinity kcal/mol RMSD Å

PDB ID Paper Vina AD4 Vina AD4 Vina AD4 Vina AD4

1S0J Amaya (2004) Y Y Y (conf. 1) Y -9.9 -13.55 0.000 1.3672AH2 Amaya (2004) Y Y N Y -6.0 -10.55 0.000 2.261

1S0I Amaya (2004) Y Y Y (conf. 1) N -8.3 -9.65 0.000 4.504

1MR5 Buschiazzo (2002) N N No

Ligand - - - - -

1MS8 Buschiazzo (2002) Y Y Y (conf. 1) Y -7.4 -9.47 0.000 2.100

1MS5 Buschiazzo (2002) Y N No

Ligand - - - - -

1MS9 Buschiazzo (2002) Y Y Y Y -7.8 -9.84 0.000 2.707

1MS3 Buschiazzo (2002) N N No

Ligand - - - - -

1MS4 Buschiazzo (2002) N N No

Ligand - - - - -

1MS0 Buschiazzo (2002) N N Two

Ligands - - - - -

Experimental Ligand crystal (Yellow)Vina Docking (Red)AutoDock4.0 Docking (Pink)

1S0J - Trypanosoma cruzi trans-sialidase in complex with MuNANA (Michaelis complex)

1MS8 - Triclinic form of Trypanosoma cruzi trans-sialidase, in complex with 3-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA)

Experimental Ligand crystal (Yellow)Vina Docking (Red)AutoDock4.0 Docking (Pink)

1MS9 - Triclinic form of Trypanosoma cruzi trans-sialidase, in complex with lactose

Experimental Ligand crystal (Yellow)Vina Docking (Red)AutoDock4.0 Docking (Pink)

Results – 1S0J• The best structures were used for docking:• Top Ranking binding energies, 1S0J:• -----------------------------------------------------------------------------------------• Rank File Name Binding Affinity kcal/mol• -----------------------------------------------------------------------------------------• 1 TPD.71184833541_out.pdbqt -13.6• 2 TPD.91185766573_out.pdbqt -12.6• 3 TPD.281010096476_out.pdbqt -12.3• 4 TPD.281011317462_out.pdbqt -12.3• 5 TPD.71184834376_out.pdbqt -12.2• 6 TPD.281010461515_out.pdbqt -12.1• 7 TPD.91186211040_out.pdbqt -12.1• 8 TPD.101185345882_out.pdbqt -12.0• 9 TPD.281011318172_out.pdbqt -12.0• 10 TPD.281011317061_out.pdbqt -11.8

Results – 1MS8• The best structures were used for docking:• Top Ranking binding energies, 1MS8:• -----------------------------------------------------------------------------------------• Rank File Name Binding Affinity kcal/mol• -----------------------------------------------------------------------------------------• 1 TPD.91185766573_out.pdbqt -14.4• 2 TPD.281010096476_out.pdbqt -13.8• 3 TPD.71184833541_out.pdbqt -12.7• 4 TPD.281011409415_out.pdbqt -12.4• 5 TPD.281011409716_out.pdbqt -12.4• 6 TPD.71184834376_out.pdbqt -12.3• 7 TPD.91186211040_out.pdbqt -11.7• 8 TPD.281011297903_out.pdbqt -11.6• 9 TPD.281011398209_out.pdbqt -11.6• 10 TPD.281011399613_out.pdbqt -11.6

Results – 1MS9• The best structures were used for docking:• Top Ranking binding energies, 1MS9:• -----------------------------------------------------------------------------------------• Rank File Name Binding Affinity kcal/mol• -----------------------------------------------------------------------------------------• 1 TPD.91185766573_out.pdbqt -14.4• 2 TPD.281010096476_out.pdbqt -13.8• 3 TPD.71184833541_out.pdbqt -12.7• 4 TPD.281011409415_out.pdbqt -12.4• 5 TPD.281011409716_out.pdbqt -12.4• 6 TPD.71184834376_out.pdbqt -12.3• 7 TPD.91186211040_out.pdbqt -11.7• 8 TPD.281011297903_out.pdbqt -11.6• 9 TPD.281011398209_out.pdbqt -11.6• 10 TPD.281011399613_out.pdbqt -11.6

Top 3 Results

• Consistently these three compounds are ranked top three across the different trans-sialidase pdb files:• dihalenaquinolide A (CSN: 71184833541)• (+)-Ovigeridimerin (CSN: 91185766573)• Bisisodiospyrin (CSN: 281010096476)

Dihalenaquinolide A• Catalogue number for Taiwanese Pharmaceutical Database,

CSN: 71184833541• Vina docking result: -13.6 kcal/mol• AutoDock 4.0 docking result: -15.23 kcal/mol• Agreement between Vina and AutoDock 4.0 alignment

Vina (Yellow)AutoDock 4.0 (Red)

Vina (Yellow)AutoDock 4.0 (Red)

(+)-Ovigeridimerin• Catalogue number for Taiwanese Pharmaceutical Database,

CSN: 91185766573• Vina docking result: -12.6 kcal/mol• AutoDock 4.0 docking result: -13.5 kcal/mol

Vina (Yellow)AutoDock 4.0 (Red)

Vina (Yellow)AutoDock 4.0 (Red)

Bisisodiospyrin• Catalogue number for Taiwanese Pharmaceutical Database,

CSN: 281010096476• Vina docking result: -12.3 kcal/mol • AutoDock 4.0 docking result: -15.73 kcal/mol

Vina (Red)AutoDock 4.0 (Pink)

Vina (Red)AutoDock 4.0 (Pink)

Cultural Fun

Wo ai Taiwan

I Would Like to Extend a Thanks to...University of California, San Diego

• Gabriele Wienhausen

• Peter Arzberger

• Dr. Phil Bourne

• Chirag Krishna

National Taiwan University

• Dr. Jung-Hsin Lin

• Dr. Jung-Hsin Lin’s lab, and finally

Tosh Nomura Eureka! Foundation for making this trip possible